# A Reactive Antagonist Strategy: Cysteine‐Directed Covalent Molecular Glue in Plant Hormone Receptor Regulation

## TL;DR

Scientists developed a new chemical strategy to selectively activate plant hormone signaling by targeting specific protein interactions, enabling precise control of complex biological pathways.

## Contribution

A reactive antagonist strategy was introduced to selectively promote COI1 binding to a cysteine-mutated JAZ variant while blocking wild-type JAZs.

## Key findings

- O-bromo-ethyl COR-oxime selectively binds to Cys-mutated JAZ1 and induces its degradation in Arabidopsis.
- The RA strategy enables subtype-specific activation of jasmonate signaling without affecting endogenous pathways.
- The approach provides a tool for dissecting complex signaling networks in systems with genetic redundancy.

## Abstract

Controlling protein–protein interactions (PPIs) remains a challenge in modern chemistry. In plants, jasmonoyl‐L‐isoleucine (JA‐Ile) acts as a molecular glue that facilitates PPIs between the F‐box protein COI1 and JAZ repressors, leading to transcriptional reprogramming. However, the functional redundancy of JAZ proteins complicates biological studies. To overcome this, we introduce a reactive antagonist (RA) strategy that selectively induces COI1‐JAZ interactions for a Cys‐mutated JAZ mutant while inhibiting interactions with wild‐type JAZs. We designed and synthesized COR‐oxime derivatives, identifying O‐bromo‐ethyl COR‐oxime as an optimal RA, functioning as a Cys‐directed covalent molecular glue. Mass spectrometry and fluorescence anisotropy assays confirmed its selective covalent binding to Cys‐mutated JAZ1, leading to targeted degradation in Arabidopsis. This strategy enables precise functional dissection of JAZ subtypes without affecting endogenous pathways. Given the genetic redundancy in many biological systems, the RA strategy provides a powerful chemical biology tool for dissecting complex signaling networks beyond plant hormone research.

The plant hormone jasmonate is perceived by COI1‐JAZ co‐receptors comprising a single F‐box protein COI1 and multiple JAZ repressors with overlapping functions, complicating genetic analysis. We present a reactive antagonist (RA) strategy that selectively promotes COI1 binding to a cysteine‐engineered JAZ variant while blocking wild‐type JAZs, enabling subtype‐specific activation of jasmonate signaling.